This invention relates to novel organic compound and methods for their synthesis. More particularly, the invention relates to novel compounds affecting lymphatic absorption of cholesterol.
Atherosclerosis is a major cause of heart attack, stroke, and gangrene of the extremities and can be attributed directly to having high levels of cholesterol in the body. Cholesterol can enter the body by absorption from foods by the intestinal mucosal cells and the lymphatic system (i.e., exogenous sources). Cholesterol also is produced in the liver by a sequence of enzymatic reactions (i.e., endogenous biosynthesis). Endogenous biosynthesis of cholesterol involves a key enzyme, HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase. HMG-CoA reductase inhibitors can be used to lower total plasma cholesterol in patients with primary hypercholesterolemia. Effective inhibition of HMG-CoA reductase is realized by drugs such as Lovastatin (sold as Mevacor from Merck Co.), Mevalotin (from Sankyo Co., Japan), and analogs thereof (e.g., compounds sold under the trade names Sivastatin, Mevastatin, and Pravastatin). Exogenous sources of cholesterol, however, are not affected by these drugs. Various compounds have been reported to be useful for lowering cholesterol absorption. See, e.g., U.S. Pat. Nos. 5,246,960, 5,175,186, 5,215, 972, 5,495,048, 5,856,503, and 5,637,771. Currently, a lipase inhibitor termed Xenical(copyright) has been offered for obesity management. Xenical(copyright) has been reported to achieve a slight reduction in cholesterol.
The invention features a compound of Formula I: 
R1 can be independently hydrido, halo, alkyl, alkenyl, alkylyl, haloalkyl, hydroxyalkyl, hydroxy, alkoxy, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, aryl, heterocyclic, heteroaryl, alkylsulfonyl, arylsulfonyl, N-alkylsulfamyl, N,N-dialkylsulfamyl, N-arylsulfomyl, N-alkyl-N-arylsulfamyl, carboxy, carboxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, amido, N-alkylamido, N-N-dialkylamido, N-monoarylamido, N-alkyl-N-arylamido, N-alkyl-N-hydroxyamido, N-alkyl-N-hydroxyamidoalkyl, amidoalkyl, aminoalkyl, alkylaminoalkyl, amidino, cyanoamidino, heterocycloalkyl, aralkyl, cycloalkyl, cycloalkenyl, alkylthio, alkylsulfinyl, N-alkylamino, N,N-dialkylamino, acyl, acyloxy, aryloxy, acylamino, amino, cyano, nitro, sulfonate, alkylsilyl, phenylselenyl, thiol, arylsulfenyl, alkylsulfenyl, arylsulfinyl, or alkylsilyloxy.
R2 can be independently hydrido, halo, alkyl, alkenyl, alkylyl, haloalkyl, hydroxyalkyl, hydroxy, alkoxy, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, aryl, heterocyclic, heteroaryl, alkylsulfonyl, arylsulfonyl, N-alkylsulfamyl, N,N-dialkylsulfamyl, N-arylsulfomyl, N-alkyl-N-arylsulfamyl, carboxy, carboxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, amido, N-alkylamido, N-N-dialkylamido, N-monoarylamido, N-alkyl-N-arylamido, N-alkyl-N-hydroxyamido, N-alkyl-N-hydroxyamidoalkyl, amidoalkyl, aminoalkyl, alkylaminoalkyl, amidino, cyanoamidino, heterocycloalkyl, aralkyl, cycloalkyl, cycloalkenyl, alkylthio, alkylsulfinyl, N-alkylamino, N,N-dialkylamino, acyl, acyloxy, aryloxy, acylamino, amino, cyano, nitro, sulfonate, alkylsilyl, or phenylselenyl, thiol, arylsulfenyl, alkylsulfenyl, arylsulfinyl, or alkylsilyloxy;
R3 can be independently hydrido, halo, alkyl, alkenyl, alkylyl, haloalkyl, hydroxyalkyl, hydroxy, alkoxy, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, aryl, heterocyclic, heteroaryl, alkylsulfonyl, arylsulfonyl, N-alkylsulfamyl, N,N-dialkylsulfamyl, N-arylsulfomyl, N-alkyl-N-arylsulfamyl, carboxy, carboxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, amido, N-alkylamido, N-N-dialkylamido, N-monoarylamido, N-alkyl-N-arylamido, N-alkyl-N-hydroxyamido, N-alkyl-N-hydroxyamidoalkyl, amidoalkyl, aminoalkyl, alkylaminoalkyl, amidino, cyanoamidino, heterocycloalkyl, aralkyl, cycloalkyl, cycloalkenyl, alkylthio, alkylsulfinyl, N-alkylamino, N,N-dialkylamino, acyl, acyloxy, aryloxy, acylamino, amino, cyano, nitro, sulfonate, alkylsilyl, phenylselenyl, thiol, arylsulfenyl, alkylsulfenyl, arylsulfinyl, or alkylsilyloxy.
R4 can be independently hydrido, alkyl, or hydroxyalkyl.
R5 can be independently hydrido, alkyl, or hydroxyalkyl.
In some embodiments, R1 is halo, R2 and R3 are hydroxy, and R4 and R5 are alkyl in the compound, e.g., R1 is chloro and R4 and R5 are methyl. In other embodiments, R1 is halo, R2 and R3 are alkylsilyloxy, and R4 and R5 are alkyl, e.g., R1 is chloro, R2 and R3 are OSi-t-BuMe2, and R4 and R5 are methyl. In one embodiment, the compound has Formula (24): 
The invention also features a compound of Formula II: 
R1 can be independently any of the groups described above for R1 of Formula I. R2 can be independently any of the groups described above for R2 of Formula I. R3 can be independently any of the groups described above for R3 of Formula I. R4 can be independently hydrido, alkyl, or hydroxyalkyl. R5 can be independently hydrido, alkyl, or hydroxyalkyl. However, when R1 is chloro, R2 and R3 are not hydroxy and R4 and R5 are methyl.
In some embodiments, R1 is halo, R2 and R3 are hydroxy, and R4 and R5 are alkyl. In some embodiments, R1 is halo, R2 and R3 are alkylsilyloxy; and R4 and R5 are alkyl, e.g., R1 is chloro, R2 and R3 are OSi-t-BuMe2, and R4 and R5 are methyl.
The invention also features a compound of Formula III: 
In these compounds, R1 can be independently any of the groups described above for R1 of Formula I.
R2 can be independently any of the groups described above for R2 of Formula I. R3 can be independently any of the groups described above for R3 of Formula I. R4 can be independently hydrido, alkyl, or hydroxyalkyl. R5 can be independently hydrido, alkyl, or hydroxyalkyl.
In some embodiments, R1 is halo, R2 and R3 are selected from hydroxy and alkylsilyloxy, and R4 and R5 are alkyl, e.g., R1 is chloro, R2 and R3 are hydroxy, and R4 and R5 are methyl. In some embodiments, R1 is halo, R2 and R3 are alkylsilyloxy, and R4 and R5 are methyl, e.g., R1 is chloro, R2 and R3 are OSi-t-BuMe2, and R4 and R5 are methyl. In some embodiments the compound has Formula (23): 
The invention also features a compound of Formula IV: 
R1 can be independently any of the groups described above for R1 of Formula I. R2 can be independently any of the groups described above for R2 of Formula I. R3 can be independently any of the groups described above for R3 of Formula I. R4 can be independently hydrido, alkyl, or hydroxyalkyl. R5 can be independently hydrido, alkyl, or hydroxyalkyl. R6 can be independently hydrido, hydroxy, or acyloxy. R7 can be independently alkyl, or arylselenylalkyl.
In some embodiments, R1 is halo, R2 and R3 are selected from hydroxy, alkylsilyloxy, or aralkyloxy, R4 and R5 are alkyl, R6 is selected from hydrido, hydroxy, or acyloxy, and R7 is selected from alkyl or arylselenylalkyl, e.g., R1 is chloro; R2 and R3 are OSi-t-BuMe2, R4 and R5 are methyl, R6 is hydrido, and R7 is methyl. In other embodiments, R1 is chloro, R2 and R3 are hydroxy, R4 and R5 are methyl, R6 is hydrido, and R7 is methyl. In some embodiments, R1 is chloro; R2 and R3 are arylalkyloxy; R4 and R5 are methyl, R6 is hydroxy, and R7 is arylselenylalkyl. In some embodiments, R1 is chloro,; R2 and R3 are arylalkyloxy, and R4 and R5 are methyl, R6 is acyloxy, and R7 is arylselenylalkyl. In some embodiments, R1 is chloro, R2 and R3 are arylalkyloxy; R4 and R5 are methyl, R6 is acyloxy, and R7 is methyl.
The invention also features a compound of Formula V: 
R1 can be independently any of the groups described above for R1 of Formula I. R2 can be independently any of the groups described above for R2 of Formula I. R3 can be independently any of the groups described above for R3 of Formula I. R4 can be independently hydrido, alkyl, or hydroxyalkyl. R5 is independently hydrido, alkyl, or hydroxyalkyl. R6 can be hydroxy. R8 can be independently hydroxy, or alkylsilyloxy.
In some embodiments, R1 is halo; R2 and R3 are arylalkyloxy; R4 and R5 are alkyl; R6 is hydroxy; and R8 is selected from hydroxy and alkylsilyloxy, e.g., R1 is chloro; R2 and R3 are OBn; and R4 and R5 are methyl; R6 is hydroxy; and R8 is OSi-tBuMe2. In some embodiments, R1 is chloro; R2 and R3 are OBn; R4 and R5 are methyl; R6 is hydroxy; and R8 is hydroxy.
The inventions also features a method of synthesizing a compound of Formula I: 
wherein R1 is chloro, R2 and R3 are hydroxy, and R4 and R5 are methyl. The method comprises reacting compound (4) with compound (3) to form intermediate compound (18). 
wherein R9 is OSi-t-BuMe2, X1 is chloro, X2 is bromo; 
wherein R1 is chloro, R2 and R3 are OSi-tBuMe2. The method further comprises isolating compound (18) and deprotecting compound (18). The result is a compound of Formula I.
The invention also features a method of synthesizing (+) chloropuupehenone. The method comprises hydrogenating compound (19) to form compound (25). 
Desilylation of compound (25) forms compound (26). 
Oxidation of compound (26) forms (+) chloropuupehenone (27). 
The invention also features a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of Formula 1: 
The composition can be in the form of a capsule or a liquid emulsion. The composition can in a controlled release formulation, e.g., a dispersion in hydroxypropylmethyl cellulose, or in a formulation suitable for parenteral administration, e.g., a lipid emulsion. The composition can comprise a diluent such as polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, or benzyl alcohol. The pharmaceutically-acceptable carrier material can be lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, povidone, polyvinylpyrrolidone, or polyvinyl alcohol.
The invention also features a method for identifying a compound that inhibits lymphatic absorption of cholesterol. The method comprises administering a known amount of cholesterol and a compound of claim 1 to a non-human mammal, and determining the amount of administered cholesterol that is absorbed by the lymph. A statistically significant decrease in lymphatic cholesterol absorption relative to the lymphatic cholesterol absorption of a corresponding control mammal indicates that the compound is effective for inhibiting lymphatic absorption of cholesterol. A statistically insignificant change or a statistically significant increase in lymphatic cholesterol absorption relative to the lymphatic cholesterol absorption of a corresponding control mammal indicates the compound does not inhibit lymphatic absorption of cholesterol. The cholesterol and the compound can be administered in a lipid emulsion.
The invention also features a method of treating a cholesterol-related condition. The method comprises administering an effective amount of a compound of Formula I to a mammal. The cholesterol-related condition can be, for example, atherosclerosis, hypercholesterolemia, heart attack, gangrene, and stroke. The compound can be administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly, or topically, and in an amount from about 4 mg/kg to about 4 g/kg of body weight per day. The compound can be administered in a composition as described above. The method can be part of a treatment regimen comprising a diet low in cholesterol, or as part of a treatment regimen that includes administering an HMG-CoA reductase inhibitors. The method can be used to treat humans. The method can include administering the compound for 7 days or more, e.g., for one year or more.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.